Treatment of Skin Aging and Photoaging with Innovative Oral Dosage Forms of Non-Hydrolized Carnosine and Carcinine

Aging is a multifactorial process resulting in several functional and esthetic changes in the skin. Advances in research have yielded a tremendous amount of information on the molecular pathways involved in both intrinsic aging (natural) and extrinsic aging (including photoaging). Some of the characteristic features of aging skin, such as wrinkling, loss of elasticity, and atrophy, can largely be attributed to dermal changes. The amount of collagen in the skin decreases, while the cross linking increases, and the solubility of collagen is reduced. The role of fibroblasts in aging tissue has been most extensively studied in mammalian skin. The total number of fibroblasts decreases, and their metabolism shows characteristic alterations.The dermis is maintained in large part by fibroblasts, which secrete dermal collagens, elastin, and other extracellular matrix components. When the skin is wounded, fibroblasts secrete proteases to degrade the wounded matrix, and then synthesize new matrix. The fibroblasts also secrete growth factors to stimulate the keratinocytes to proliferate and close the wound and cytokines to attract macrophages to engulf and degrade debris. Stress-induced premature senescence (SIPS) occurs after many different sublethal stresses including a number of oxidation factors, such as H2 O2 , hyperoxia, or organic and lipid hydroperoxides. Fibroblast cells in replicative senescence share common features with cells in SIPS: morphology, senescence-associated beta-galactosidase activity, cell cycle regulation, gene expression and telomere shortening. Most human cells lack sufficient telomerase to maintain telomeres, hence these genetic elements shorten with time and stress, contributing to aging and disease. We systematically examine the evidence supporting the use of dosage forms of non-hydrolized carnosine or carcinine in oral formulations for skin beautification purposes and provide a summary of the biomarkers of intrinsic and extrinsic skin aging, including photoaging. Senescence phenotype of human diploid fibroblasts is related with the exhaustion of their proliferative potential. This work suggests that different cell types, such as human skin fibroblasts, may use specific cellular treatment strategies with imidazole-containing dipeptides to halt the accelerated senescence of the fibroblast cells in response to telomere attrition and thus prevent skin aging through the number of biologically viable and safe metabolic pathways. The published data demonstrate that telomerase is expressed in the epidermis in situ independent of age. The reason for the sustained telomere length or expression of telomerase activity in the epidermis is associated not only with an increased turnover of keratinocytes, but also occurs due to the fact that the formation of a well structured epidermis strictly depends on a tight balance between proliferation and differentiation. Oral dosage forms of non-hydrolized carnosine or carcinine induce cellular responses in human skin fibroblasts through the telomere-mediated pathway and redox signaling, supporting the view that carnosine or related imidazole-containing dipeptide based compound-induced hormetic stimulation of cellular antioxidant defenses can be a useful approach toward anti-aging intervention to the skin

Early Ahmed Glaucoma Valve Implantation after Penetrating Keratoplasty Leads to Better Outcomes in an Asian Population with Preexisting Glaucoma

To evaluate the efficacy of Ahmed Glaucoma Valve (AGV) surgery and the optimal interval between penetrating keratoplasty (PKP) and AGV implantation in a population of Asian patients with preexisting glaucoma who underwent PKP.In total, 45 eyes of 45 patients were included in this retrospective chart review. The final intraocular pressures (IOPs), graft survival rate, and changes in visual acuity were assessed to evaluate the outcomes of AGV implantations in eyes in which AGV implantation occurred within 1 month of post-PKP IOP elevation (Group 1) and in eyes in which AGV implantation took place more than 1 month after the post-PKP IOP evaluation (Group 2). Factors that were associated with graft failure were analyzed, and the overall patterns of complications were reviewed. By their final follow-up visits, 58% of the patients had been successfully treated for glaucoma. After the operation, there were no statistically significant differences between the groups with respect to graft survival (p = 0.98), but significant differences for IOP control (p = 0.049) and the maintenance of visual acuity (VA) (p<0.05) were observed. One year after surgery, the success rates of IOP control in Group 1 and Group 2 were 80% and 46.7%, respectively, and these rates fell to 70% and 37.3%, respectively, by 2 years. Factors that were associated with a high risk of AGV failure were a diagnosis of preexisting angle-closure glaucoma, a history of previous PKP, and a preoperative IOP that was >21 mm Hg. The most common surgical complication, aside from graft failure, was hyphema.Early AGV implantation results in a higher probability of AGV survival and a better VA outcome without increasing the risk of corneal graft failure as a result of post-PKP glaucoma drainage tube implantation

Characteristic Metabolism of Free Amino Acids in Cetacean Plasma: Cluster Analysis and Comparison with Mice

From an evolutionary perspective, the ancestors of cetaceans first lived in terrestrial environments prior to adapting to aquatic environments. Whereas anatomical and morphological adaptations to aquatic environments have been well studied, few studies have focused on physiological changes. We focused on plasma amino acid concentrations (aminograms) since they show distinct patterns under various physiological conditions. Plasma and urine aminograms were obtained from bottlenose dolphins, pacific white-sided dolphins, Risso's dolphins, false-killer whales and C57BL/6J and ICR mice. Hierarchical cluster analyses were employed to uncover a multitude of amino acid relationships among different species, which can help us understand the complex interrelations comprising metabolic adaptations. The cetacean aminograms formed a cluster that was markedly distinguishable from the mouse cluster, indicating that cetaceans and terrestrial mammals have quite different metabolic machinery for amino acids. Levels of carnosine and 3-methylhistidine, both of which are antioxidants, were substantially higher in cetaceans. Urea was markedly elevated in cetaceans, whereas the level of urea cycle-related amino acids was lower. Because diving mammals must cope with high rates of reactive oxygen species generation due to alterations in apnea/reoxygenation and ischemia-reperfusion processes, high concentrations of antioxidative amino acids are advantageous. Moreover, shifting the set point of urea cycle may be an adaption used for body water conservation in the hyperosmotic sea water environment, because urea functions as a major blood osmolyte. Furthermore, since dolphins are kept in many aquariums for observation, the evaluation of these aminograms may provide useful diagnostic indices for the assessment of cetacean health in artificial environments in the future

Lipid (per) oxidation in mitochondria:an emerging target in the ageing process?

Lipids are essential for physiological processes such as maintaining membrane integrity, providing a source of energy and acting as signalling molecules to control processes including cell proliferation, metabolism, inflammation and apoptosis. Disruption of lipid homeostasis can promote pathological changes that contribute towards biological ageing and age-related diseases. Several age-related diseases have been associated with altered lipid metabolism and an elevation in highly damaging lipid peroxidation products; the latter has been ascribed, at least in part, to mitochondrial dysfunction and elevated ROS formation. In addition, senescent cells, which are known to contribute significantly to age-related pathologies, are also associated with impaired mitochondrial function and changes in lipid metabolism. Therapeutic targeting of dysfunctional mitochondrial and pathological lipid metabolism is an emerging strategy for alleviating their negative impact during ageing and the progression to age-related diseases. Such therapies could include the use of drugs that prevent mitochondrial uncoupling, inhibit inflammatory lipid synthesis, modulate lipid transport or storage, reduce mitochondrial oxidative stress and eliminate senescent cells from tissues. In this review, we provide an overview of lipid structure and function, with emphasis on mitochondrial lipids and their potential for therapeutic targeting during ageing and age-related disease

Carnosine:can understanding its actions on energy metabolism and protein homeostasis inform its therapeutic potential?

The dipeptide carnosine (β-alanyl-L-histidine) has contrasting but beneficial effects on cellular activity. It delays cellular senescence and rejuvenates cultured senescent mammalian cells. However, it also inhibits the growth of cultured tumour cells. Based on studies in several organisms, we speculate that carnosine exerts these apparently opposing actions by affecting energy metabolism and/or protein homeostasis (proteostasis). Specific effects on energy metabolism include the dipeptide's influence on cellular ATP concentrations. Carnosine's ability to reduce the formation of altered proteins (typically adducts of methylglyoxal) and enhance proteolysis of aberrant polypeptides is indicative of its influence on proteostasis. Furthermore these dual actions might provide a rationale for the use of carnosine in the treatment or prevention of diverse age-related conditions where energy metabolism or proteostasis are compromised. These include cancer, Alzheimer's disease, Parkinson's disease and the complications of type-2 diabetes (nephropathy, cataracts, stroke and pain), which might all benefit from knowledge of carnosine's mode of action on human cells. © 2013 Hipkiss et al.; licensee Chemistry Central Ltd

Different experimental approaches in modelling cataractogenesis: An overview of selenite-induced nuclear cataract in rats

Cataract, the opacification of eye lens, is the leading cause of blindness worldwide. At present, the only remedy is surgical removal of the cataractous lens and substitution with a lens made of synthetic polymers. However, besides significant costs of operation and possible complications, an artificial lens just does not have the overall optical qualities of a normal one. Hence it remains a significant public health problem, and biochemical solutions or pharmacological interventions that will maintain the transparency of the lens are highly required. Naturally, there is a persistent demand for suitable biological models. The ocular lens would appear to be an ideal organ for maintaining culture conditions because of lacking blood vessels and nerves. The lens in vivo obtains its nutrients and eliminates waste products via diffusion with the surrounding fluids. Lens opacification observed in vivo can be mimicked in vitro by addition of the cataractogenic agent sodium selenite (Na2SeO3) to the culture medium. Moreover, since an overdose of sodium selenite induces also cataract in young rats, it became an extremely rapid and convenient model of nuclear cataract in vivo. The main focus of this review will be on selenium (Se) and its salt sodium selenite, their toxicological characteristics and safety data in relevance of modelling cataractogenesis, either under in vivo or in vitro conditions. The studies revealing the mechanisms of lens opacification induced by selenite are highlighted, the representatives from screening for potential anti-cataract agents are listed

Drug Design of Mitochondria-Targeted Antioxidants, Action, Metabolism and Perspectives for Ophthalmic Therapeutics: N-acetylcarnosine Codrug Treatment Platform

Maintaining the redox balance within the mitochondria is critical for cellular homeostasis in the eye since the mitochondria host the energy producing systems of the cell and it is widely recognized that damage to the mitochondria plays a key role in sight threatening age-related eye disorders, including retinopathies (maculodystrophy, retinitis pigmentosa , hereditary optic neuropathy), as well as glaucoma, cataract, and autoimmune uveitis. Reactive oxygen species (ROS) are generated as by-products of cellular metabolism, primarily in the mitochondria. Although ROS are essential participants in cell signaling and regulation, when their cellular production overwhelms the intrinsic antioxidant capacity, damage to cellular macromolecules such as DNA, proteins, and lipids ensues. Oxidized phospholipids play an important role in execution of the mitochondrial stage of apoptosis and clearance of apoptotic cells. During the lipid peroxidation (LPO) reaction, lipid hydroperoxides are formed as primary products. Several lines of evidence suggest that lipid hydroperoxides can trigger cell death in many cell types, which may be mediated by mitochondria dysfunction pathway. Recently, there was a breakthrough in mitochondrial targeting of antioxidants. Mitochondrial function can be manipulated selectively by targeting bioactive compounds to mitochondria in living cells. Lipophylic antioxidants were covalently coupled to a triphenylphosphonium cation, and these compounds were preferentially taken up by mitochondria. In this work we proposed the combined use of mitochondria-targeted antioxidant mito Vit E and N-acetylcarnosine, an ophthalmic prodrug of L-carnosine in patented formulation of eye drops including the mucoadhesive compound carboxymethylcellulose to help elucidate the role of mitochondrial oxidative damage in apoptotic cell death. We suggest that mitochondrial oxidative damage plays an important role in ROS-induced apoptosis. Further work using these and other mitochondrially targeted compounds to dissect out the role of mitochondrial oxidative changes in peroxide-induced apoptosis is ongoing. The findings reported demonstrate that mitochondrially targeted antioxidants such as mito vit E + N-acetylcarnosine in the eye drop formulation with carboxymethylcellulose can be used to investigate the role of mitochondrial oxidative stress in retinal neuronal cells (RGCs) death and may represent a new pharmacologic tool to mitigate complex ocular pathology for the treatment of sight-threatening eye diseases and, especially, neurodegeneration originating from an oxidative injury and glaucomatous neurodegeneration. This strategy also has potential for unraveling the contribution of oxidative stress to other ocular pathologies involving mitochondrial dysfunction